Melanoma is of neuroectodermal origin and has a high propensity to invade and metastasize, particularly to neural-origin tissue, such as the central nervous system and brain, which often contributes to its poor prognosis (1). Desmoplastic melanoma (DM) is a subtype of cutaneous melanoma, with distinct clinico-pathologic characteristics that distinguish it from other cutaneous melanomas (2). DMs often arise in sun-exposed areas, especially the head and neck region, and have a greater propensity for invasion of nerves and aggressive local growth (3, 4). Reports have shown more frequent local recurrence of DMs compared to non-desmoplastic cutaneous melanomas (5). A distinction between DMs and non-DMs has been reported. However, no reported studies have analyzed mechanisms of neurotropism or local aggressiveness of DMs or non-DMs.
RET (REarranged during Transfection) is a proto-oncogene that encodes a receptor tyrosine kinase (RTK) (6-9). RET contains four cadherin-related motifs and a cysteine-rich region in the extracellular domain (8, 10). GDNF, a major ligand of RET, is a growth factor that facilitates the survival of dopaminergic neurons of the midbrain (11, 12). This neurotrophic factor binds to the extracellular domain of RET through the formation of a complex with glycosyl-phosphatidylinositol-anchored coreceptor (GFRα1-3), a member of the GDNF receptor family that can bind to GDNF and RET (10). Expression of GFRα3 is higher in DMs than non-DMs (13), but has not been linked to neurotropism of DMs.
Activation of RET induces signaling through the RAS-BRAF-ERK, phosphatidylinositol 3-kinase (PI3K)-Akt, and p38 mitogen-activated protein kinase (MAPK) pathways that activate various functions in cells (10). Activation of both the RET-RAS-BRAF-ERK and RET-PI3K-Akt pathways has been implicated in cell proliferation or survival, whereas the RET-PI3K pathway has been related more to cell motility (FIG. 1) (10, 14). All oncogenic mutations of RET gene, which are reported to be in cysteine-rich region or tyrosine kinase domain (intracellular domain), are ligand-independently active and reportedly responsible for development of multiple endocrine neoplasia 2A and 2B, familial medullary thyroid carcinoma, and papillary thyroid carcinoma (15-17). G691S RET mutation (RETmt) is a polymorphic nucleotide alteration in exon 11 of the juxtamembrane region of RET and enhances the response of RET against GDNF in pancreatic cancer (18).
BRAF mutations are well-documented, and are frequent in non-DMs (19). The most frequent BRAF mutation is a polymorphism in exon 15, V600E (19, 20). BRAF belongs to the RAF family of serine-threonine kinases and is a component of the RET-RAS-BRAF-MAPK kinase (MEK)-ERK signaling pathway (21). This signaling pathway is a membrane-to-nucleus signaling system controlling cell proliferation and other functions in mammalian cells (22). Although V600E BRAF mutation (BRAFmt) is suggested to cause abnormal proliferation of melanoma cells (23), the role of RETmt alone and with BRAFmt in cutaneous melanoma is unknown.